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In 208 children with opsoclonus-myoclonus syndrome (OMS), CSF IgG oligoclonal bands (OCB) and 22 immunomarkers in CSF and 21 in serum/blood were measured. In 36 untreated OMS, 58% were OCB(+), whereas 55% of treated OMS were OCB(-). OCB positivity or negativity did not alter concentrations or frequencies of immunomarkers. The phenotypes of OCB(+) and OCB(-) patients were not distinctive. CSF B cells were expanded in untreated OMS regardless of OCB positivity. These data reveal a much higher frequency of OCB positivity in untreated OMS than previously realized and a disconnect between intrathecal OCB and inflammatory mediator production., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Rituximab (anti-CD20) has been used as B-cell-targeted intervention to treat opsoclonus-myoclonus syndrome. Due to isolated reports of chronic hypogammaglobulinemia and B lymphopenia following rituximab in several disorders, and rapid B-cell depletion after a few doses, we reduced the dosage 20% in our clinical practice., Methods: In this Institutional Review Board-approved retrospective study, 32 children with opsoclonus-myoclonus syndrome and cerebrospinal fluid B-cell expansion had received front-loaded adrenocorticotropic hormone, intravenous immunoglobulin, and rituximab combination immunotherapy for de novo opsoclonus-myoclonus syndrome. Parametric statistical analysis compared 10 children receiving 1200 mg/m 2 of rituximab (300 mg/m 2 × 4) and 22 receiving 1500 mg/m 2 (375 mg/m 2 × 4). Clinical response had been video documented and scored by a blinded observer., Results: In both groups, motor severity (total score) lessened by ≥76% and cerebrospinal fluid B cells were similarly depleted (≥95%) six months after treatment. None of the treated patients remained unable to walk independently. Serum IgM depletion was analogous in the 1200 mg/m 2 (-73%) and 1500 mg/m 2 group (-64%). The relapse frequency was similar in both groups. Side effects were principally steroidal, tolerable, and transient. Circulating B-cell repopulation was comparable., Conclusions: The reduced-dose of rituximab in rituximab combination immunotherapy was as effective and well tolerated as the standard dose, and provided rapid, early therapeutic intervention in opsoclonus-myoclonus syndrome. Pending a long-term prospective study, these are proof-of-concept data in support of challenging the dose of rituximab in various disorders, which may have different dose requirements., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Pediatric opsoclonus-myoclonus syndrome (OMS) presents a paradox of etiopathogenesis: A neuroblastic tumor (NB) is found in only one half of the cases, the others are ascribed to infections or designated as idiopathic., Method: From an IRB-approved observational study of 356 US children with OMS, secondary analysis of "etiology" and related factors was performed on a well-characterized cohort. The "Tumor" (n = 173) and "No Tumor" groups (n = 183), as defined radiologically, were compared according to multiple factors considered potentially differentiating. Data were analyzed retrospectively using parametric and nonparametric tests as indicated., Results: Patients with NB were not distinguishable by prodromal symptoms, OMS onset age, gender, race/ethnicity, OMS severity, rank order of neurological sign appearance, or geographic distribution. Various CSF immunologic biomarker abnormalities of OMS did not vary in the presence or absence of a detectable tumor: frequency of six lymphocyte subsets, or concentrations of 18 cytokines/chemokines, cytokine antagonists, chemokine receptors, cell adhesion molecules, or neuronal/glial markers. Prior responsiveness to conventional immunotherapy was not contingent on tumor/no tumor designation., Conclusions: Multiple convergent factors provide compelling empirical evidence and rationalize the concept that OMS is one neurological disorder, regardless of apparent etiology. Limitations to the current clinical etiologic classifications as paraneoplastic, parainfectious/post-infectious, and idiopathic etiology require antigen-based biological solutions to tease out the molecular pathophysiology of viral/tumoral mechanisms. Systematic studies, regardless of presumed etiology, will be necessary to find the highest-yield combination of imaging approaches, screening for infectious agents, and new biomarkers. Two testable hypotheses for future research are presented., (© 2018 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Studies of cerebrospinal fluid (CSF) γδ T cells in children are limited, due especially to the lack of control data. In adults, gamma/delta T cells (TCR-γδ) residing in the intrathecal space are sometimes involved in neuroinflammation. To evaluate the possible role of γδ T cells in paediatric neuroinflammation, we immunophenotyped cerebrospinal fluid (CSF) and blood lymphocytes using flow cytometry in a case-control study of 100 children with non-inflammatory neurological disorders (NIND), 312 with opsoclonus-myoclonus (OMS) and 23 with other inflammatory neurological disorders (OIND). In NIND, the negative correlation between CSF γδ T cell frequency and patient age was striking: median frequency of 27% in infants and 3·3% in teens. Interindividual variations were largest in the youngest. There was no gender effect. In all OMS, after correcting for age, only a small effect of OMS severity remained. Measurement of markers for γδ T cell activation [human leucocyte antigen D-related (HLA-DR)], maturation (CD45RA, CD45RO) or intracellular cytokine staining [interleukin (IL)-4, interferon (IFN)-γ] failed to discriminate OMS and NIND groups. Of seven OMS immunotherapies/combinations, none altered the frequency of total CSF γδ T cells or subsets significantly. In OIND, the CSF γδ T cell frequency was < 10% for single samples of other paraneoplastic disorders [anti-neuronal nuclear antibody (ANNA)-1, PCA-1, teratoma-associated syndrome], cerebellar ataxia (post-infectious, ataxia-telangiectasia), acute disseminated encephalomyelitis, neuroborreliosis and encephalitis. This study provides new insights into CSF γδ T cells in the paediatric population. Although their role in CSF remains elusive, the negative age correlation, resistance to immunotherapy and our age cut-off references for NIND are important findings for the design of future paediatric studies., (© 2018 British Society for Immunology.)

Objective: To assess the role of microglia and macrophages in neuroinflammatory disorders in children via biomarkers, and establish control reference ranges., Methods: In an IRB-approved case-control study of 98 children, the concentrations of CSF/serum CHI3L1, sCD14, and sCD163 were measured by ELISA. Groups were controls (non-inflammatory neurological disorders, NIND, n=37), opsoclonus-myoclonus syndrome (OMS, n=37), and other inflammatory neurological disorders (OIND, n=24)., Results: In control CSF, median concentrations (ng/ml) were 25 (IQR 16,41) for CHI3L1 and 42 (26,160) for sCD14; in serum, 16 (12,22) for CHI3L1, and 431 (270,957) for sCD163. The median CSF concentration of CHI3L1 in OIND was significantly higher than controls (2.9-fold, P<0.0001) and OMS (1.6-fold higher than controls, NS). The CSF sCD14 concentration was 1.9-fold higher in OIND (P=0.008) and 1.4-fold higher in OMS than controls. sCD163, below detection limits in CSF, was not significantly increased in OIND or OMS sera., Conclusions: CSF CHI3L1 and sCD14 elevations hold promise as immunomarkers in pediatric OIND, especially in high-expression individuals. These results provide evidence of innate immune system involvement in several pediatric neuroinflammatory disorders. Pediatric control data on CSF microglia/macrophage activation markers are hereby available for other investigators., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Pediatric-onset opsoclonus-myoclonus syndrome (OMS) is a devastating neuroinflammatory, often paraneoplastic, disorder. The objective was to characterize demographic, clinical, and immunologic aspects in the largest cohort reported to date. Cross-sectional data were collected on 389 children in an IRB-approved, observational study at the National Pediatric Myoclonus Center. Non-parametric statistical analysis was used. OMS manifested in major racial/ethnic groups, paralleling US population densities. Median onset age was 1.5 years (1.2-2 interquartile range), inclusive of infants (14%), toddlers (61%), and youngsters (25%). The higher female sex ratio of 1.2 was already evident in toddlers. Time to diagnosis was 1.2 months (0.7-3); to treatment, 1.4 months (0.4-4). Irritability/crying dominated prodromal symptomatology (60%); overt infections in <35%. Acute cerebellar ataxia was the most common misdiagnosis; staggering appeared earliest among 10 ranked neurological signs ( P  < 0.0001). Some untreated youngsters had no words (33%) or sentences (73%). Remote neuroblastic tumors were detected in 50%; resection was insufficient OMS treatment (58%). Age at tumor diagnosis related to tumor type ( P  = 0.004) and stage ( P  = 0.002). A novel observation was that paraneoplastic frequency varied with patient age-not a mere function of the frequency of neuroblastoma, which was lowest in the first 6 months of life, when that of neuroblastoma without OMS was highest. The cerebrospinal fluid (CSF) leukocyte count was minimally elevated in 14% (≤11/mm 3 ) with normal differential, and commercially screened serum autoantibodies were negative, but CSF oligoclonal bands (OCB) and B cells frequency were positive (58 and 93%). Analysis of patients presenting on immunotherapy revealed a shift in physician treatment practice patterns from monotherapy toward multi-agent immunotherapy ( P  < 0.001); the number of agents/sequences varied. In sum, a major clinical challenge is to increase OMS recognition, prevent initial misdiagnosis, and shorten time to diagnosis/treatment. The index of suspicion for an underlying tumor must remain high despite symptoms of infection. The disparity in onset age of neuroblastoma frequency with that of neuroblastoma with OMS warrants further studies of potential host/tumor factors. OMS neuroinflammation is best diagnosed by CSF OCB and B cells, not by routine CSF or commercial antibody studies.

Using a panel of seven brain cell-specific biomarkers in cerebrospinal fluid (CSF), pediatric opsoclonus-myoclonus syndrome (OMS) (n=234) was compared to pediatric non-inflammatory neurological controls (n=84) and other inflammatory neurological disorders (OIND) (n=44). Only CSF NFL was elevated in untreated OMS versus controls (+83%). It was 87% higher in OIND than in OMS. On combination treatment with front-loaded ACTH, IVIg, rituximab, median CSF NFL decreased by 60% to control levels. These biochemical data suggest neuronal/axonal injury in some children with OMS without indicators of astrogliosis, and reduction on sufficient immunotherapy., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Identifying and blocking chemokine inflammatory mediators in pediatric opsoclonus-myoclonus syndrome (OMS) is critical to the treatment of this autoimmune, paraneoplastic, neurological disorder. In a prospective, case-control, clinico-scientific study of children with OMS compared to non-inflammatory neurological controls and other inflammatory neurological disorders, CCL19 (n=369) and CCL21 (n=312) were quantified in CSF and serum, respectively, by ELISA. Both cross-sectional and longitudinal effects of OMS and various immunotherapies were evaluated. Significant upregulation of CCL21 concentration (mean ± SD) (+32%) was found in serum of untreated OMS (630 ± 133 pg/mL), compared to controls (478 ± 168 pg/mL), (p<0.0001). Both corticosteroids and ACTH (corticotropin) significantly lowered CCL21 to control levels, as they did in combination with IVIg, rituximab, cyclophosphamide or other treatments, without additional reduction attributable to the other agents. In a pilot longitudinal study of ACTH-based triple therapy, the mean serum CCL21 concentration fell 59% from elevated to less than 1 SD below controls 1 week after high-dose ACTH, gradually returning to the control mean with ACTH tapering by 3 weeks and out to 12 weeks (p<0.0001). In contrast, CCL19, detectable in CSF, was not significantly altered by OMS or various immunotherapies. In the "high" CCL21 subgroup, higher serum concentrations of CCL22 (+57%) and CXCL13 (+40%), as well as the CSF concentration of BAFF (+64%), also were found. Elevated serum CCL21, not CSF CCL19, correlates with OMS severity and duration in pediatric OMS. Corticosteroids and ACTH were the only immunotherapies evaluated that down-regulated CCL21 production. Validation studies are needed to assess treatment biomarker status., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

To define cytokine concentrations and detectability in children with noninflammatory neurological disorders (NIND). The multiplex bead assay technology was used for simultaneous measurement of 34 soluble cytokines/chemokines in cerebrospinal fluid (CSF) from 73 NIND. Sera from 36 healthy children and 37 NIND also were analyzed. In CSF, CXCL10 had the highest concentration; CCL2, CXCL10, and interleukin (IL)-6 were detectable in all samples, and CXCL8, CCL22, CXCL1, IL-16, and IL-1 receptor antagonist were found in ≥50% of the samples. In serum, CXCL1 had the highest concentration; sIL-2Ra, CXCL1, CXCL10, and CCL22 were detectable in all samples, and CCL2, IL-12, CCL5, and granulocyte monocyte colony-stimulating factor (GM-CSF) were found in ≥50% of the samples. The mean CSF:serum ratio for CCL2 was several-fold higher than the rest, with the CXCL10 and CXCL8 ratios also >1. Intercorrelations between CSF cytokines included CCL2 versus CXCL8 and IL-6, and CXCL1 versus CCL22, reflecting both T-helper-1 (Th1)/Th1 and Th1/Th2 relations. Serum correlations included CCL11 versus CCL2, GM-CSF, and IL-4. For serum cytokines, the agreement between healthy children and NIND was good, with the exception of higher CCL4 in NIND. Cytokines in children varied greatly in concentration and detectability, with chemokines predominating in the CSF. These data allow investigators to select their own kit cytokines, instead of manufacturer-selected cytokines, for greater cost-effectiveness and interpretability.

Opsoclonus-myoclonus syndrome (OMS) is a neuroinflammatory disorder associated with remote cancer. To understand more clearly the role of inflammatory mediators, the concentration of CXCR3 ligands CXCL10, CXCL9 and CXCL11 was measured in 245 children with OMS and 81 paediatric controls using enzyme-linked immunosorbent assay (ELISA), and CXCR3 expression on CD4(+) T cells was measured by flow cytometry. Mean cerebrospinal fluid (CSF) CXCL10 was 2·7-fold higher in untreated OMS than controls. Intrathecal production was demonstrated by significantly different CXCL10 CSF : serum ratios. The dichotomized 'high' CSF CXCL10 group had higher CSF leucocyte count (P = 0·0007) and B cell activating factor (BAFF) and CXCL13 concentrations (P < 0·0001). CSF CXCL10 did not correlate with clinical severity or relapse using grouped data, although it did in some patients. Among seven types of immunotherapy, including rituximab or chemotherapy, only adrenocorticotrophic hormone (ACTH) monotherapy showed reduced CSF CXCL10, but prospective longitudinal studies of ACTH combination therapies indicated no reduction in CXCL10 despite clinical improvement (P < 0·0001). CXCL10 concentrations were 11-fold higher in CSF and twofold higher in serum by multiplexed fluorescent bead-based immunoassay than enzyme-linked immunosorbent assay, but the two correlated (r = 0·7 and 0·83). In serum, no group differences for CXCL9 or CXCL11 were found. CXCR3 expression on CD4(+) T cells was fivefold higher in those from CSF than blood, but was not increased in OMS or altered by conventional immunotherapy. These data suggest alternative roles for CXCL10 in OMS. Over-expression of CXCL10 was not reduced by clinical immunotherapies as a whole, indicating the need for better therapeutic approaches., (© 2013 British Society for Immunology.)

Purpose: To study the role of Th2-attracting chemokines in opsoclonus-myoclonus syndrome (OMS), a serious neurological paraneoplastic disorder in need of better immunological understanding and therapy., Methods: The CCR4 agonists CCL22 and CCL17 were measured in serum by ELISA in children with OMS (238 and 260, respectively), pediatric controls (115 and 143), and other inflammatory neurological disorders (33 and 24)., Results: Both CCL22 (+55 %) and CCL17 (+121 %) were significantly elevated in untreated OMS compared to controls and inter-correlated (p < 0.0001). Their concentrations in untreated OMS also were higher than in OIND (21 %, 41 %). The concentration of CCL22 in ACTH and steroids groups (not IVIg) was 51 % lower than in controls, but only a smaller effect of ACTH on CCL17 was found. Prospective longitudinal studies revealed a precipitous 81 % drop in CCL22 even by the first week of high-dose ACTH therapy, staying below control mean for at least 12 weeks, and a 34 % reduction after 8 months of combined treatment. Response to ACTH was dose-related (r = -0.50, p < 0.0001). Luminex detection confirmed the ELISA results for CCL22, which were about 200 % higher., Conclusions: These data reveal an elevated serum concentration of Th2-attracting chemokines CCL22 and CCL17 in OMS. Marked and rapid reduction in CCL22, not CCL17, with either ACTH or steroid therapy suggests differential regulation and cellular sources of CCR4 ligands, and CCL22 as a potential candidate biomarker for ACTH or corticosteroid effect.

Objective: To test for hypothesized disease- and treatment-induced changes in cytokines and adhesion molecules in children with opsoclonus-myoclonus syndrome (OMS)., Methods: Multiplex bead assay technology was used for simultaneous measurement of 34 soluble cytokines in cerebrospinal fluid (CSF) and serum. Soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) were measured by ELISA. In total, there were 388 children (239 OMS, 114 controls, and 35 other inflammatory neurological disorders (OIND))., Results: In untreated OMS, mean CSF IL-6 was elevated 2.3-fold, but 67-fold in OIND, without significant differences in other CSF cytokines. Mean serum concentrations of sIL-2Ra (+50%) and CXCL1 (+70%) (p<0.0001) were also raised. CSF CCL5 was more often detected in untreated OMS than controls (p=0.005), as was serum CCL11 and IL-13 in treated OMS. Mean CSF CCL4 and IL-1Ra were selectively higher in IVIg-treated OMS (p≤0.0001). CSF sICAM-1 was elevated only in OIND (3.3-fold); serum sICAM-1 was higher in untreated OMS (+21%); and sVCAM-1 was not affected. No correlations with OMS severity or duration were identified., Conclusions: Novel cytokine, cytokine antagonist, and soluble adhesion molecule abnormalities due to OMS or treatment were found. However, the normality of much of the data strengthens previous findings implicating B cell mechanisms., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: B-cell dysregulation has been implicated but not fully characterized in pediatric opsoclonus-myoclonus syndrome (OMS), a neuroblastoma-associated neuroinflammatory disorder., Objective: To assess the role of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), two critical B cell-modulating cytokines, as potential biomarkers of disease activity and treatment biomarkers in OMS., Methods: Soluble BAFF and APRIL were measured in cerebrospinal fluid (CSF) and serum by ELISA in 433 children (296 OMS, 109 controls, 28 other inflammatory neurological disorders (OIND)). BAFF-R receptors on circulating CD19+ B cells were measured by flow cytometry. A blinded scorer rated motor severity on the OMS Evaluation Scale. Immunotherapies were evaluated cross-sectionally and longitudinally., Results: The mean CSF BAFF concentration, which was elevated in untreated OMS and OIND, correlated with OMS severity category (P = 0.006), and reduction by adrenocorticotropic hormone or corticotropin (ACTH) (-61%) or corticosteroids (-38%) was seen at each level of severity. In contrast, CSF APRIL was normal in OMS and OIND and unaffected by immunotherapy. When the entire OMS dataset was dichotomized into 'high' versus 'normal' CSF BAFF concentration, the phenotype of the high group included greater motor severity and number of CSF oligoclonal bands, and a higher concentration of inflammatory chemokines CXCL13 and CXCL10 in CSF and CXCL9 and CCL21 in serum. Serum APRIL was 6.7-fold higher in the intravenous immunoglobulins (IVIg) group, whereas serum BAFF was 2.6-fold higher in the rituximab group. The frequency of B cell BAFF-R expression was similar in untreated and treated OMS. Longitudinal studies of CSF BAFF revealed a significant decline in ACTH-treated patients (with or without rituximab) (P < 0.0001). Longitudinal studies of serum APRIL showed a 2.9-fold increase after 1 to 2 g/kg IVIg monotherapy (P = 0.0003)., Conclusions: Striking distinctions in BAFF/APRIL signaling were found. OMS displayed heterogeneity in CSF BAFF expression, which met many but not all criteria as a potential biomarker of disease activity. We speculate that CSF BAFF may have more utility in a biomarker panel than as a stand-alone biomarker, and that the selective upregulation of both serum APRIL by IVIg and BAFF by rituximab, as well as downregulation of CSF BAFF by ACTH/steroids, may have utility as treatment biomarkers.

To study aberrant B cell trafficking into the CSF in opsoclonus-myoclonus syndrome (OMS), chemoattractants CXCL13 and CXCL12, and B cell frequency and CXCR5 expression, were evaluated. CSF CXCL13 concentration and the CSF/serum ratio were higher in untreated OMS than controls, related directly to OMS severity and inversely to OMS duration, and correlated with CSF B cell frequency and oligoclonal bands. CXCL12 showed the opposite pattern. Selective accumulation of CXCR5+ memory B cells in CSF was found. In ACTH-treated OMS, CXCL13, but not CXCL12, was lower. These data implicate the chemokine/chemoreceptor pair CXCL13/CXR5 in B cell recruitment to the CNS in OMS. CXCL13 and CXCL12 may serve as reciprocal biomarkers of disease activity, but CXCL13 also had utility as a treatment biomarker., (Copyright © 2011 Elsevier B.V. All rights reserved.)